Abstract: The long term objective of this application to understand distinct signaling pathways of vascular endothelial growth factor (VEGF), also know as vascular permeability factor (VPF) receptors, in the pathogenesis of cardiovascular disease. We now know that VEGF receptors are not only expressed in endothelial cells (ECs) but are expressed in several non-endothelial cells like stem cells where they control pathophysiological non- angiogenesis processes. In this grant cycle we will focus on how VEGF-B and its receptors, neuropilin-1 (NRP1) in cardiomyocytes play a protective role in cardiomyopathy, whereas in endothelial cells NRP1 in connection with IFN?R1 promotes proinflammatory response. To test our hypothesis, we have proposed three specific aims. In Aim 1, we will examine the molecular pathways of VEGF-B/NRP1-mediated cardioprotection in CMs both in vitro and in two different cardiomyopathy disease process, myocardial infarction (MI) and virus induced-inflammatory cardiomyopathy (myocarditis) in both mouse and zebrafish models. In Aim 2, we will investigate the role of endothelial cell NRP1 (NRP1EC) in MI and myocarditis using an inducible EC-specific NRP1 knockout mice and zebrafish models. We will also define the regulatory role of IFN?/NRP1EC on inflammatory chemokines in cardiac ECs and related downstream signaling pathwya. Finally, in Aim 3 we will test whether we can treat inflammatory cardiac diseases by boosting mitochondrial function. In this regard, we will use (-) Epicatechin (Epi), which promotes mitochondrial function, to reverse the inflammation and cardiomyopathy in the two models. Epi is derived from plant-based chemicals, particularly from cocoa. Secondly, we will also use anti-CXCL10 antibodies to inhibit the inflammatory responses in similar models. Finally we will test whether combining both Epi and anti-CXCL10 antibody can inhibit advance stages of cardiomyopathy. Overall our proposed study will reveal the molecular mechanism of VEGF-B/NRP1CM as well IFN?R1/NRP1EC signaling in MI and myocarditis and will identify a novel treatment strategy for patients with cardiomyopathy. In addition, the unique pathways and therapeutic strategies that will be developed in this proposal may apply to other chronic inflammatory conditions that affect the heart like atherosclerosis and autoimmune diseases.